%0 Journal Article %J Am J Med Genet A %D 2017 %T Neonatal fractures as a presenting feature of LMOD3-associated congenital myopathy. %A Abbott, Megan %A Jain, Mahim %A Pferdehirt, Rachel %A Chen, Yuqing %A Tran, Alyssa %A Duz, Mehmet B %A Seven, Mehmet %A Gibbs, Richard A %A Muzny, Donna %A Lee, Brendan %A Marom, Ronit %A Burrage, Lindsay C %K Female %K Fractures, Bone %K Homozygote %K Humans %K Infant, Newborn %K Male %K Microfilament Proteins %K Muscle Proteins %K Mutation %K Myopathies, Structural, Congenital %K Pedigree %X

Nemaline myopathy is a rare inherited disorder characterized by weakness, hypotonia, and depressed deep tendon reflexes. It is clinically and genetically heterogeneous, with the most severe phenotype presenting as perinatal akinesia, severe muscle weakness, feeding difficulties and respiratory failure, leading to early mortality. Pathogenic variants in 12 genes, encoding components of the sarcomere or factors related to myogenesis, have been reported in patients affected with the disorder. Here, we describe an early, lethal presentation of decreased fetal movements, hypotonia, muscle weakness, and neonatal respiratory failure requiring ventilator support in three siblings from a consanguineous family. All exhibited perinatal fractures, and thus, a skeletal dysplasia was considered as possibly contributing to the phenotype. However, whole exome sequencing revealed a homozygous, loss-of-function pathogenic variant in LMOD3, which has recently been associated with nemaline myopathy and, in a subset of patients, perinatal fractures. This case demonstrates the importance of considering congenital neuromuscular disorders in the differential diagnosis of perinatal fractures.

%B Am J Med Genet A %V 173 %P 2789-2794 %8 2017 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/28815944?dopt=Abstract %R 10.1002/ajmg.a.38383 %0 Journal Article %J Am J Med Genet A %D 2012 %T WDR35 mutation in siblings with Sensenbrenner syndrome: a ciliopathy with variable phenotype. %A Bacino, Carlos A %A Dhar, Shweta U %A Brunetti-Pierri, Nicola %A Lee, Brendan %A Bonnen, Penelope E %K Amino Acid Sequence %K Base Sequence %K Bone and Bones %K Craniosynostoses %K Cytoskeletal Proteins %K Ectodermal Dysplasia %K Exome %K Female %K Hedgehog Proteins %K Homozygote %K Humans %K Infant %K Intracellular Signaling Peptides and Proteins %K Male %K Mutation %K Mutation, Missense %K Pedigree %K Phenotype %K Proteins %K Siblings %X

Sensenbrenner syndrome and unclassified short rib-polydactyly conditions are ciliopathies with overlapping phenotypes and genetic heterogeneity. Mutations in WDR35 were identified recently in a sub-group of patients with Sensenbrenner syndrome and in a single family that presented with an unclassified form of short-rib polydactyly (SRP) syndrome. We report on siblings with an unusual combination of phenotypes: narrow thorax, short stature, minor anomalies, developmental delay, and severe hepatic fibrosis leading to liver failure and early death in two of the children. Both parents were unaffected suggesting autosomal recessive inheritance. The family and their affected children were followed over a decade. Exome sequencing was performed in one affected individual. It showed a homozygous missense mutation in a highly conserved position of the WDR35 gene. This family represents a WDR35-ciliopathy with a complex clinical presentation that includes significant overlap of the phenotypes described in Sensenbrenner syndrome and the unclassified SRPs. The accurate molecular diagnosis of this family exemplifies the power of exome sequencing in the diagnosis of Mendelian disorders and enabled us to broaden and refine our understanding of Sensenbrenner syndrome and SRP. Detailed genotype-phenotype information is provided as well as discussion of previously reported cases.

%B Am J Med Genet A %V 158A %P 2917-24 %8 2012 Nov %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/22987818?dopt=Abstract %R 10.1002/ajmg.a.35608